Methods and systems for monitoring and obtaining information of at least one portion of a sample using conformal laser therapy procedures, and providing electromagnetic radiation thereto

ABSTRACT

In one exemplary embodiment of the present invention, method and system can be provided for obtaining information associated with at least one portion of a sample. For example, a temperature change can be caused in the portion of the sample. At least one first electro-magnetic radiation can be forwarded to a section near or in the portion of the sample. A deformation of the section can be identified at a plurality of depths as a function of (i) a phase of at least one second electro-magnetic radiation provided from the section, and/or (ii) a rate of change of the phase and/or an amplitude of the second electro-magnetic radiation. In another exemplary embodiment of the present invention, method and system can be provided for controlling a temperature distribution in a sample. For example, an electro-magnetic radiation can be provided to the section in the sample at a particular wavelength. The temperature distribution can be controlled by modifying the particular wavelength of the electro-magnetic radiation when the electro-magnetic radiation is provided to the section.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is based upon and claims the benefit of priority fromU.S. Patent Application Ser. No. 60/764,622, filed Feb. 1, 2006 and U.S.Patent Application Ser. No. 60/810,445, filed Jun. 1, 2006, the entiredisclosures of which are incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

The invention was made with the U.S. Government support under ContractNo. 17-02-2-0006 awarded by the US Department of the Army CooperativeAgreement (DAMD). Thus, the U.S. Government has certain rights in theinvention.

FIELD OF THE INVENTION

The present invention relates to systems and methods for monitoring atleast one portion of a sample using conformal laser therapy procedures,providing electromagnetic radiation thereto and obtaining informationassociated with at least one characteristic of the sample.

BACKGROUND OF THE INVENTION

A use of lasers for ablating or thermally destroying diseased tissue isknown and at time preferred, primarily due to the potential for preciselocal effect with minimal collateral damage. In practice, however, lasertherapy has been less than perfect for use in certain clinicalapplications, such as the treatment of early epithelial cancers andtheir precursors. One of the problems with laser therapy for theseapplications has been the inability to accurately control and guide thetreatment depth, resulting in either disease recurrence due toincomplete therapy or complications associated with overly aggressivetreatment.

Epithelial Cancer: Diagnosis and Treatment

Methods and techniques for identifying and treating cancer at an earlystage have been widely pursued as offering the potential to dramaticallydecrease the morbidity and mortality associated with metastasis. Sinceepithelial cancers and precursor lesions are frequently focal and can bedistributed heterogeneously across a wide field, a sensitive diagnosisis extremely demanding. A diagnosis should be rendered on the size scaleof a single cell in a field comprising possibly more than a billioncells.

Epithelial cancer also presents challenges for therapy. Since they aresuperficial, access to epithelial lesions can frequently be obtainedthrough the use of minimally invasive catheters or endoscope. Thetherapeutic challenge, however, is in comprehensively killing, resectingor ablating the entire lesion without damage to underlying or adjacenttissues. This is particularly challenging since the depth of disease andeven the thickness of normal epithelial layers can vary substantially.Additionally, epithelial tissues are highly compliant and therapeuticinstrumentation can result in significant compression. As a result,therapies designed to affect tissue to a fixed depth risk eitherunder-treatment resulting in recurrence, or over-treatment that can leadto significant complications.

Barrett's Esophagus

The importance of Barrett's esophagus (BE) is based primarily on theprevalence of this disease, the rapid increase in its incidence, and thedismal prognosis for patients with high-grade dysplasia andadenocarcinoma. as described in publication 1 identified below. Thecurrent consensus (as described in publications 2 and 3 identifiedbelow) holds that comprehensive destruction of BE in a controlledfashion, along with anti-reflux treatment, results in squamous regrowthand that continued reflux control prevents the return of BE. Thechallenge is in achieving comprehensive removal of the pathologicmucosa, while preserving the underlying tissues of the esophageal wall.Treatment that is incomplete can result in a squamous overgrowth thatmasks underlying pathology. Overly aggressive therapy can result instricture or perforation of the esophageal wall. Provided below is theinformation relating to screening and therapy of BE.

Screening

Several approaches for esophageal screening in the management of BE havebeen investigated. Brush cytology (as described in publications 4 and 5identified below) and the use of biological markers, such as thedeletion and/or mutation of the 17p (p53) gene, (as described inpublications 6 and 7 identified below) can be used independently ofendoscopy but cannot provide spatial mapping of disease. Highmagnification video endoscopy (as described in publication 8 identifiedbelow), fluorescence spectroscopy (as described in publications 9identified below), and light-scattering spectroscopy (as described inpublications 10 identified below) each show promise for point diagnoses,but provide insufficient information regarding subsurface microstructureand have not been demonstrated for wide-field screening. High-resolutionendoscopic ultrasound and chromoendoscopy (as described in publications11 and 12 identified below, respectively) can both be applied to a widefield, but have suffered from low sensitivity and specificity.

Optical coherence tomography (OCT) system, methods and techniques (asdescribed in publications 13 and 14 identified below) has beendeveloped. Certain accurate OCT diagnostic criteria have been developedfor specialized intestinal metaplasia, dysplasia and adenocarcinoma, asdescribed in International Patent Application PCT/US2004/029148, filedSep. 8, 2004, U.S. patent application Ser. No. 10/501,276, filed Jul. 9,2004, and publications 15-17 identified below. For example, advances inOCT technology have occurred demonstrating that the acquisition of anOCT signal in the wavelength domain (as opposed to the time domain) canprovide orders of magnitude improvement in imaging speed whilemaintaining excellent image quality, as described in publications 18-20identified below. One such exemplary second-generation imagingtechnology has been developed, e.g., optical frequency domain imaging(OFDI), as described in U.S. patent application Ser. No. 11/266,779,filed Nov. 2, 2005 and publication 21 identified below. With OFDImethods, techniques and systems, high-resolution ranging can beconducted in a tissue by detecting spectrally-resolved interferencebetween the tissue sample and a reference while the source wavelength istuned. (See, e.g., publication 22 identified below). Currently, OFDImethods, techniques and systems may be capable of capturing (e.g., 10μm) 3 voxels at rates of approximately 40 million per second and theimaging speeds may likely be more than double in the near future, asprovided in publication 23 identified below. Additionally,phase-sensitive OFDI methods, techniques and systems has been used forimaging flow, as provided in publication 24 identified below.

Controllable Therapy

Certain endoluminal approaches have been evaluated for the treatment ofSIM (with and without dysplasia), including photodynamic therapy (PDT)(as provided in reference 25 identified below), laser (532 nm and 1064nm) (as provided in reference 26 identified below), multipolarelectrocoagulation (as provided in reference 27 identified below), argonplasma coagulation (as provided in reference 28 identified below),endoscopic mucosal resection (as provided in reference 29 identifiedbelow), radiofrequency ablation (as provided in reference 30 identifiedbelow) and cryoablation (as provided in reference 31 identified below)using liquid nitrogen. Although each of these techniques appear to besuccessful, most studies describe non-uniform therapy that canpotentially result in persistent SIM or excessively deep ablation,resulting in stricture or perforation. In a study of over 100 patients,PDT may result in a stricture rate of 30% for single treatments and 50%for more than one treatment (as provided in reference 32 identifiedbelow). An exemplary reason for failure is not entirely clear butpossible contributing causes include the operator-dependent nature ofmany of these hand-held, hand-aimed devices, the large surface area thatrequires treatment and the inherent preference for aphysician-determined visual end point for the treatment (as provided inreferences 3 and 30 identified below). Additionally, a high variabilitymay exist in the thickness of mucosal layers within and between patientsand have directly observed significant compression of the soft tissuesof the esophagus. The prior therapeutic approaches, however, do notaccount for the variability of layer thickness or compressibility of theesophageal wall.

Accordingly, there is a need to overcome the deficiencies describedherein above.

OBJECTS AND SUMMARY OF THE INVENTION

To address and/or overcome the above-described problems and/ordeficiencies as well as other deficiencies, exemplary embodiments ofmethods and systems can be provided for monitoring at least one portionof a sample using conformal laser therapy procedures, providingelectromagnetic radiation thereto and obtaining information associatedwith at least one characteristic of the sample.

Such deficiencies can be addressed using the exemplary embodiments ofthe present invention. In one exemplary embodiment of the presentinvention, a method and system are provided for obtaining informationassociated with at least one portion of a sample. For example, atemperature change can be caused in the portion of the sample. At leastone first electro-magnetic radiation can be forwarded to a section nearor in the portion of the sample. A deformation of the section can beidentified at a plurality of depths as a function of (i) a phase of atleast one second electro-magnetic radiation provided from the section,and/or (ii) a rate of change of the phase and/or an amplitude of thesecond electro-magnetic radiation.

It is possible to generate an interferometric signal associated with thesecond electro-magnetic radiation, and determine the phase of the secondelectro-magnetic radiation using the interferometric signal. Theinterferometric signal can be measured as a function of a wavelength ofthe second electro-magnetic radiation. The first electro-magneticradiation can have a wavelength that varies over time. The temperaturechange may be caused using a laser arrangement. A border can be definedbetween the at least one changed portion and an unchanged portion of thesample as a function of the information associated with the deformation.The sample can be a biological structure, and the changed portion may bedenatured, damaged and/or destroyed. In addition, an interferometricsignal associated with the second electro-magnetic radiation can begenerated, and the amplitude of the second electro-magnetic radiationcan be determined using the interferometric signal. The interferometricsignal can be measured as a function of a wavelength of the secondelectro-magnetic radiation.

In another exemplary embodiment of the present invention, a method andsystem are provided for controlling a temperature distribution in asample. For example, an electro-magnetic radiation can be provided tothe section in the sample at a particular wavelength. The temperaturedistribution can be controlled by modifying the particular wavelength ofthe electro-magnetic radiation when the electro-magnetic radiation isprovided to the section.

In particular, the modification to the particular wavelength can changea distribution of damage in at least one portion of the sample. Thetemperature distribution can be further controlled by modifying a powerof the electro-magnetic radiation. The particular wavelength may bemodified to be in a range of approximately (i) about 1.35 μm to 1.5 μmand/or (ii) about 1.7 μm to 2.2 μm. The temperature distribution can besubstantially due to an absorption of the electro-magnetic radiation bywater. The electro-magnetic radiation can be provided by a thulium laseramplifier arrangement and/or an erbium laser amplifier arrangement. Arate at which the particular wavelength is modified can be greater thatabout 10 nm per second. The particular wavelength may be modified in anon-random manner.

These and other objects, features and advantages of the presentinvention will become apparent upon reading the following detaileddescription of embodiments of the invention, when taken in conjunctionwith the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

Further objects, features and advantages of the present invention willbecome apparent from the following detailed description taken inconjunction with the accompanying figures showing illustrativeembodiments of the present invention, in which:

FIG. 1A is a schematic diagram of an OFDI balloon catheter in accordancewith an exemplary embodiment of the present invention;

FIG. 1B is a photograph of the OFDI balloon catheter shown in FIG. 1A;

FIG. 2A is an exemplary image of a perspective view of a swine esophagusobtained using the OFDI balloon catheter in accordance with an exemplaryembodiment of the present invention;

FIG. 2B is an exemplary image of a top view of the swine esophagus ofFIG. 2A;

FIG. 2C is an exemplary image of a side view of a wall of the swineesophagus of FIG. 2A;

FIG. 3 is an exemplary OFDI image acquired in a human subject using a BEtechnique in accordance with an exemplary embodiment of the presentinvention;

FIG. 4 is a schematic diagram of exemplary arrangement and usage thereoffor treating and monitoring tissue in accordance with an exemplaryembodiment of the present invention;

FIG. 5 is a set of multiple exemplary m-mode OFDI phase images obtainedusing the exemplary arrangement of FIG. 4 together with a correspondinghistology;

FIGS. 6A-6D are exemplary images associated with the OFDI data acquiredfor a translating sample in accordance with the exemplary embodiment ofthe present invention;

FIG. 7A is an exemplary pre-laser treatment OFDI image obtained usingthe exemplary embodiment of the present invention;

FIG. 7B is an exemplary pre-laser treatment birefringence image obtainedusing the exemplary embodiment of the present invention;

FIG. 7C is an exemplary post-laser treatment OFDI image obtained usingthe exemplary embodiment of the present invention;

FIG. 7D is an exemplary post-laser treatment birefringence imageobtained using the exemplary embodiment of the present invention;

FIG. 8 is an image of an exemplary vascular map extrated from acomprehensive dataset obtained from porcine esophagus in-vivo which canbe obtained using the exemplary embodiment of the present invention;

FIG. 9 is an exemplary in-vivo Doppler flow image of a porcine esophagusobtained using the exemplary embodiment of the present invention;

FIG. 10 is an plot of water absorption coefficient and correspondingpenetration depth as a function of wavelength obtained using theexemplary embodiment of the present invention;

FIG. 11 is a schematic diagram of a two beam catheter probe inaccordance with another exemplary embodiment of the present invention;

FIG. 12 is schematic side and front illustrations of a three beamcatheter probe in accordance with yet another exemplary embodiment ofthe present invention;

FIG. 13 is a perspective view of a watch-spring multichannel opticalrotary junction in accordance with an exemplary embodiment of thepresent invention;

FIG. 14 is a conceptual rendering of an image which can provide feedbackto a user obtained using an exemplary embodiment of the presentinvention;

FIG. 15 is a block diagram of a sample arm of an OFDI systemincorporating an optical switch in accordance with a further exemplaryembodiment of the present invention;

FIG. 16 is a block diagram of the sample arm of the OFDI systemincorporating an optical splitter in accordance with a still furtherexemplary embodiment of the present invention;

FIG. 17 is a block diagram of the sample arm of the OFDI systemincorporating a single wavelength-division multiplexer in accordancewith yet further exemplary embodiment of the present invention;

FIG. 18 is a block diagram of the sample arm of the OFDI systemincorporating a cladding mode coupler and a dual-clad fiber inaccordance with still another exemplary embodiment of the presentinvention;

FIG. 19 is a block diagram of a three-port rotary coupler and catheterin accordance with an exemplary embodiment of the present invention;

FIG. 20 is a block diagram of a single-fiber rotary coupler withsubsequent demultiplexing of the therapy light and capable of splittingof imaging light in accordance with another exemplary embodiment of thepresent invention;

FIG. 21 is a schematic diagram and usage of a two-beam in-line catheterprobe in accordance with an exemplary embodiment of the presentinvention;

FIG. 22 are front and side illustrations of a three-beam catheter probeand balloon catheter in accordance with an exemplary embodiment of thepresent invention;

FIG. 23 is a side view of a micro-motor-based arrangement capable ofgenerating a slowly rotatable therapy beam and fast scanning imagingbeam in accordance with an exemplary embodiment of the presentinvention;

FIG. 24 is a block diagram of a therapy source incorporating a low powertunable source followed by a broadband booster amplifier in accordancewith an exemplary embodiment of the present invention;

FIG. 25 is a block diagram of a therapy source incorporating multiplelaser diodes (LDs) at difference wavelengths and polarizations inaccordance with another exemplary embodiment of the present invention;

FIG. 26 is an illustration of a wavelength-tunable therapy sourceincorporating a laser diode bar and results generated thereby inaccordance with an exemplary embodiment of the present invention;

FIG. 27 is a side view of another exemplary embodiment of a system whichincludes a galvanometric scanner which can allow the OFDI beam to berepetitively scanned across the surface of the tissue, and usagethereof;

FIG. 28 is a schematic diagram of a further exemplary embodiment of theOFDI system according to the present invention which can be used todetect both the imaging and monitoring signals via acousto-opticfrequency shifters;

FIG. 29A is a flow diagram of an exemplary embodiment of a method forobtaining information associated with at least one portion of a sampleaccording to the present invention;

FIG. 29B is a flow diagram of another exemplary embodiment of the methodfor controlling a temperature distribution in the sample according tothe present invention; and

FIG. 29C is a flow diagram of yet another exemplary embodiment of themethod for applying a laser radiation to at least one portion of abiological structure according to the present invention.

Throughout the figures, the same reference numerals and characters,unless otherwise stated, are used to denote like features, elements,components or portions of the illustrated embodiments. Moreover, whilethe subject invention will now be described in detail with reference tothe figures, it is done so in connection with the illustrativeembodiments. It is intended that changes and modifications can be madeto the described embodiments without departing from the true scope andspirit of the subject invention as defined by the appended claims.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

An exemplary embodiment of the system and method according to thepresent invention for controlling and localizing therapy can be based ona thermal excitation delivered by a conventional, spatially scannedlaser beam. For example, in the absence of photochemical or phasetransition processes, the laser energy absorbed by tissue can besubstantially or entirely converted to a temperature rise, as describedin publication 33 identified below. For exposure durations greater thanapproximately 10 ms, temperatures in excess of 60-70° C. generally canlead to irreversible protein denaturation and cell death irrespective ofduration, as described in publication 34 identified below. When theenergy is absorbed, it can be subject to a spatial redistribution by athermal diffusion. In 1983, as described in publication 35 identifiedbelow, an exemplary concept was described which provided that spatiallyconfined microsurgical effects (selective photothermolysis) can beachieved by the use of laser exposures that are shorter than thecharacteristic thermal diffusion time of the heated volume. For arelatively large (>1 mm) diameter laser beam and laser wavelengths inthe vicinity of 1450 nm, this characteristic diffusion time forbiological tissues may be on the order of 1 second. Under theseconditions, the temperature increase can be determined by the laserpower density, P_(d), the absorption coefficient, μa, and the durationof exposure t (as described in publications 33 and 34 identified below)as follows: $\begin{matrix}{{\Delta\quad{T\left( {t,r,z} \right)}} \approx {\frac{P_{d}t\quad\mu_{a}}{\rho\quad c}{\exp\left( {{{- \mu_{a}}z} - \frac{2r^{2}}{W^{2}}} \right)}}} & {{Eq}.\quad 1}\end{matrix}$where ρ is the tissue density, c the heat capacity, and r the radialdistance from the center of a Gaussian laser beam of 1/e2 radius, W.Although this approximation neglects scattering of the laser light as itpropagates into the tissue, models that explicitly include scattering(as described in publication 36 identified below) indicate less than 10%deviation from Eq. 1 under the stated conditions.

Since the absorption coefficient is wavelength-dependent, Eq. 1indicates that laser parameters P_(d), t, and wavelength can be used tocontrol the depth of thermal injury and to minimize collateral damage tounderlying tissues. Operating in the visible portion of the spectrum ischallenging since absorption is governed by a wide range of chromophoreswhose concentration is highly variable across different tissues andpathologic conditions. By comparison, the absorption spectrum ofbiological tissues near 1.45 μm may be dominated by water, and cantherefore be roughly constant across a range of tissues. Additionally,by tuning over a modest wavelength range, from 1375 nm to 1430 nm forexample, absorption lengths can be selected that range from over 2 mm to300 μm. This exemplary range is well matched to the depthscharacteristic of epithelial lesions.

Exemplary Monitoring

Several approaches have been investigated for monitoring laser therapy,including the analysis of the acoustic transients generated duringablation (as described in publication 37 identified below), changes intissue reflectivity (as described in publications 38 and 39 identifiedbelow), fluorescence spectroscopy for discrimination between plaque andvessel wall (as described in publication 40 identified below), plasmaspectroscopy to distinguish between bone and nerve tissue (as describedin publication 41 identified below), and analysis of the cavitationbubble dynamics at the tip of a laser optical probe for controlledsclera perforation in glaucoma surgery (as described in publication 42identified below). With the exception of the procedures that are basedon a reflectivity described in publications 38 and 39, in each of suchmethods, the monitoring signal arose only after the zone of thermalinjury has transitioned across a boundary of the specific tissue types.None could determine the depth of thermal injury or the spatialrelationship of the damaged tissue to adjacent viable tissue. Certaindegree of spatial resolution has been achieved by monitoring the portionof laser light that is not absorbed by the tissue. By inserting anoptical fiber through a needle, this light can be collected fromdifferent perspectives surrounding the heated volume andtemperature-dependent scattering changes can be measured (as describedin publication 43 identified below). A more direct approach,high-resolution in situ imaging, has also been demonstrated forvisualizing scattering changes and the physical removal of tissueresulting from ablative laser irradiation (as described in publication44 identified below).

Exemplary embodiments of monitoring systems, methods and techniquesaccording to the present invention may utilize information regardingwell-known tissue responses to a thermal injury. These exemplaryresponses can include, but not limited to, microscopic deformation (asdescribed in publication 33 identified below) and changes in scattering(as described in publications 36, 38 and 45 identified below),birefringence (as described in publication 46 identified below), andblood flow (as described in publication 47 identified below) that canresult from laser heating and that can be observed over a range oftemperatures beginning as low as 45° C. One exemplary aspect of anexemplary embodiment of the method and technique according to thepresent invention is that these thermal responses can be detected withhigh spatial resolution and presented in a cross-sectional image formatalong with the microscopic tissue structure.

Exemplary Strategies for Conformal Laser Therapy

According to an exemplary embodiment of the present invention, a system,arrangement and method can be provided that are capable of screening anddelivering precisely guided laser therapy. Since the characteristiclength-scales preferably usable for comprehensive screening andcomprehensive therapy are likely distinct, it is possible to separatelyperform these objectives. For example, the screening (e.g., possiblyperformed as a first step) may utilize comprehensive imagingtechnique(s) with a resolution on the cellular size-scale. Thisexemplary procedure can be used to identify regions for subsequenttherapy. After the performance of the screening procedure, theendoscopic probe can be directed back to the specified regions, andtherapy may be performed under real-time guidance so that all disease istreated and collateral damage is minimized. This exemplary result canimprove the management of patients with Barrett's esophagus by, e.g.,increasing the effectiveness of therapy while decreasing the risk ofcomplications.

Although described in conjunction with a treatment of epithelialcancers, the exemplary embodiments of the system, techniques and methodsaccording to the present invention can be applicable to any applicationof laser treatment including but not limited to, for example,applications in dermatology. Some relevant epithelial cancers andprecancerous lesions addressed by the exemplary embodiments of thepresent invention can include, but not limited to, the larynx, cervixand ovaries, bladder, oral cavity and lung. In addition, the exemplaryembodiments of the present invention can be applicable to the areas ofmonitoring photodynamic therapy, radiofrequency ablation, andcryotherapy to provide control over depth and spatial extent of therapy.

Exemplary Wide-Field Screening

In order to perform an effective screening procedure, it is preferableto conduct a comprehensive examination of large surface areas and theapplication of accurate diagnostic criteria in order to identifyspecific regions of pathology. Various OCT diagnostic criteria has beendeveloped and verified for specialized intestinal metaplasia, dysplasiaand adenocarcinoma, as describe in publications 15-17 identified below.For example, across 288 biopsies obtained from 121 patients, asensitivity and specificity for diagnosing SIM (versus all other upperGI tract tissues) has been determined of about 97% and 92%,respectively, as described in publication 16 identified below. Untilrecently, however, the exemplary OCT technique was too slow to imagelarge mucosal surface areas. As discussed herein below, advances havebeen made that may overcome this timing issue, and provide a preliminarydemonstration of comprehensive esophageal imaging in vivo.

Optical Frequency-Domain Imaging (OFDI)

As described above, publication 21 identified below describes thedevelopment of the OFDI technique as an alternative to the use of theOCT techniques. Although the light source (as discussed in publication22 and 23 identified below) and the detection principles of OFDI areuseful, the contrast, resolution and cross-sectional image presentationare approximately equivalent or similar to those provided by OCT. One ofthe advantages of OFDI is that OFDI has a higher detection sensitivity,thus enabling a significant increase in the image acquisition speed,without compromising image quality. The system used for thesepreliminary studies was designed specifically for endoscopic imaging andprovides an acquisition rate of 10,000 depth-scans (A-lines) per second,an axial resolution of 8 μm in tissue, and a ranging depth of 3.5 mm, asdescribed in publication 24 identified below. The imaging speed of thisexemplary system is limited solely by the rate at with which data can betransferred across the computer's bus and stored to a hard drive.

Exemplary Balloon Catheter

For comprehensive esophageal imaging, an exemplary embodiment of an OFDIcatheter may be provided in accordance with the present invention thatcan be centered within the esophageal lumen using a balloon sheath shownin FIGS. 1A and 1B. The exemplary catheter may include of a probescanner 2000 which can rotate, and may pull back an inner optical core2010. The inner core 2010 can be enclosed within a transparent sheath2020. At the distal end of the catheter, the balloon 2040 which, wheninflated, may center the imaging optics. The imaging beam 2030 can befocused onto the esophageal surface 2050. This imaging beam 2030 may bescanned to achieve comprehensive imaging. The balloon 2040 can have aninflated diameter of 1.8 cm, and may allow for a longitudinal imagingover a length of 4.5 cm without repositioning. The optical core 2010 ofthe catheter can include an optical fiber, a spacer for expansion of theoptical beam, a gradient index lens for focusing, and a right-angleprism for directing the beam perpendicularly to the longitudinal axis ofthe catheter. A miniature cylindrical lens was fabricated in-house andplaced on the second surface of the prism. This lens compensated forastigmatism induced by the plastic sheaths and resulted in adiffraction-limited beam (30 μm diameter) on the tissue surface. In use,the exemplary catheter may be rotated at rate of about 4 revolutions persecond, allowing the acquisition of 2500 axial scans per circularcross-section. This exemplary OFDI system can record an encoder signalto precisely track the rotation and pull-back of the catheter. Thisinformation is used in reconstructing the 3-dimensional data set.

Preliminary Porcine Esophageal Imaging

The esophageal imaging techniques can be performed in two ˜50 kg swine.Although the complete 20 GB data set may likely not be represented indiscrete figures, the information content is shown by FIGS. 2A-2C. Forexample, in a perspective view of FIG. 2A, an image 2100 provides a 3Drendering of the entire imaged esophagus. In a front view of FIG. 2B, animage 2110 illustrates a single transverse cross section of the imagedesophagus. In FIG. 2C, image 2120 shows a zoomed cross sectional imageof at least one portion of the esophagus. A sampling with a resolutionof 10 μm×20 μm×30 μm (r,θ,z) can yield a comprehensive microscopic dataset that can be displayed volumetrically a the image 2100 of FIG. 2A formapping and orientation, or in high-resolution cross-sectional images inwhich the entire esophageal wall can be visualized as the image 2110 inFIG. 2B. An expanded view of the image 2120 of FIG. 2C depicts thearchitectural structure of the mucosal layers.

Preliminary Human Esophageal Imaging

An exemplary single rotational image 2150 is shown in FIG. 3. Hallmarkfeatures of SIM (disorganized epithelial architecture with irregularsurface; presence of large epithelial glands) of a patient are showntherein. This patient had a prior diagnosis of BE, and imaging wasperformed prior to PDT.

These preliminary studies demonstrate that a) comprehensive OFDImicroscopic imaging in vivo is feasible, b) the architectural structureof the entire esophageal wall can be visualized, and c) featuresimportant to the diagnosis of SIM in human subjects can be detectedusing the balloon centering probe.

Monitoring Laser Thermal Injury

In response to heating, tissue proteins and collagen can denature,giving rise to microscopic deformation (described in publications 33identified below), increased in scattering (described in publications36, 38 and 45 identified below), reduced birefringence (described inpublication 46 identified below), and reduced blood flow (described inpublication 47 identified below). The description below provides themethods for monitoring these changes using exemplary OFDI in accordancewith the exemplary embodiments of the present invention. In theexemplary demonstration of each, freshly obtained porcine esophagussamples and duodenum samples (as a proxy for SIM) were mounted with amicroscope cover glass on the epithelial surface so that the approximatepressure and thermal conductivity of the balloon catheter could besimulated.

An exemplary embodiment of an apparatus for collecting OFDI signalsduring a laser irradiation and use thereof according to the presentinvention is shown in FIG. 4. For example, the treatment light isdelivered through a collimator 2200. The imaging light is deliveredthrough a second collimator 2220. The treatment beam 2210 and imagingbeam 2230 overlap when reaching the tissue 2270 which is covered with athink glass cover slip 2260 and resting on a backing 2280. The tissue istranslated by a motorized translation stage 2290. The imaging beam isfocused by a lens 2250. The top-down image depicting beam overlap 2250is provided. For a thermal excitation, a collimated, high-power Gaussianlaser beam (e.g., diameter=1.1 mm; wavelength=1450 nm; power=400 mW) canbe used. The OFDI sampling beam can be focused at the tissue surface to,e.g., a 1/e² intensity diameter of 23 μm and aligned so that itoverlapped with the laser spot as shown in FIG. 4. During the datacollection, the samples may be held at a fixed location and/ortranslated using a motorized stage.

Exemplary Microscopic Deformation

As laser energy is deposited in tissue, the resulting temperatureincrease can denature proteins and collagen. These changes can bemanifested by microscopic deformation that can be measured usingphase-sensitive OFDI. The following data demonstrates this capability.

Fixed spot—For such exemplary experiment, the samples were held at afixed location. OFDI depth-scans were acquired continuously at a rate ofabout 10 kHz while the 1450 nm laser was switched on, held at a constantpower of 400 mW for a predetermined duration, and switched off.Representative data for three different laser exposure durations isshown in the graphs of FIG. 5 as “M-mode” images where the vertical axis2300 a, 2300 b, 2300 c represents depth within the tissue, thehorizontal axis 2310 a, 2310 b, 2310 c denotes time and the magnitude ofthe measured phase-shift is represented using a color lookup table 2320(red=positive phase-shift; blue=negative). A red horizontal line 2330 a,2330 b, 2330 c, at the top of each phase-shift image denotes theinterval over which the laser was on. Upon initial laser exposure, asuperficial region of positive phase-shift overlying a lower region ofnegative shift has been observed. As the laser irradiation continued,the depth at which the phase transitioned from positive to negativebecame progressively deeper and the magnitude of the overlyingphase-shift decreased. No measurable phase-shift was detected after thelaser was switched off. A protein denaturation gives rise to localmicroscopic structural changes and a nidus of local deformation that isdetected as a phase-shift in the interferometric signal. As the laserexposure continues, the zone of active denaturation propagates in depthwith overlying tissues becoming completely denatured. The depth at whichthe direction of the phase-shift reverses identifies the focal center ofactive denaturation.

To verify these results, histological sections were obtained followinglaser exposure and nitro-blue tetrazolium chloride (NBTC) staining wasused to assess the extent of laser damage. NBTC stains positive forlactate dehydrogenase (LDH), which is a thermolabile enzyme; loss of LDHactivity ensues rapidly upon heat induced cell damage and is correlatedwith cell lethality (as described in publications 48 and 49 identifiedbelow). Therefore, the depth of the border between unstained and stainedtissue have been selected as the depth of laser damage. Correspondingphase-shift data and histology are shown in 2340 a, 2340 b, 2340 c. Thepreliminary findings suggest that the border between thermally denaturedtissue and viable tissue corresponds with the inflection point of thephase-shift measured with OFDI. Quantitatively, the depth-derivative ofthe phase-shift has been determined for each A-line and defined thedepth of injury as the point of maximum negative value of thederivative. The depths determined in this way are provided in FIG. 5 asvertical lines adjacent to each M-mode image and show a goodcorrespondence with histomorphometry.

Translating spot—Laser treatment of large epithelial surface areas canbe facilitated by adding a therapeutic laser beam to the existing OFDIcatheter so that the laser and OFDI beams are simultaneously scanned.The preliminary imaging studies demonstrated comprehensive esophagealimaging with an OFDI beam size of 30 μm. Obtaining a precise alignmentof >1 mm diameter laser beam on successive rotational scans shouldtherefore be obtainable. To simulate the monitoring while scanning, thecomputer-controlled translation stage 2290 (see FIG. 4) can becontrolled to repetitively toggle the sample velocity from 1.8 mm/s to0.9 mm/s.

An OFDI intensity image 2400 acquired with no laser irradiation is shownin FIG. 6A. For the images 2410, 2420 and 2430 shown in FIGS. 6B, 6C,and 6D, respectively, the 1450 nm laser power was about 400 mW. Thetranslation of the samples during the exposure resulted in a line oflaser damage across the surface of the sample. Since the thermal energydeposition can be proportional to the exposure time (see Eq. 1), thedepth of laser damage can vary along the line according to the inverseof the translation velocity. Histology sections, obtained from regionsof fast and slow translation and with an orientation perpendicular tothe line, indicated laser injury depths of 0.41 mm and 0.69 mmrespectively. The phase-shift data corresponding to the image 2410 ofFIG. 6B is illustrated as the image 2420 in FIG. 6C. In a substantialagreement with the histomorphometric measurements, the depth of thedamage determined by the phase-shift data (max negative derivative) canbe 0.40 mm and 0.67 mm in the regions of fast and slow velocity,respectively.

Speckle Decorrelation

Speckle is a phenomenon that is commonly observed when imaging withcoherent illumination and manifests as a grainy pattern of high- andlow-intensity that does not appear to correlate with the macroscopicstructure. In tissue, speckle generally arises from the interferencebetween photons that have traversed different paths during propagationwithin the sample. If the scatterers within the tissue are moving, evenon a microscopic scale, the speckle pattern is likely seen to rapidlyfluctuate. The measurements of the time-evolution of the speckle patterncan therefore provide insight into microscopic motion within the sample.This exemplary technique has been provided for investigatingbiomechanical properties (as described in publication 50 identifiedbelow), and thermal excitation (as described in publication 51identified below), in biological tissues. The extension of theseconcepts to the depth-resolved monitoring of laser tissue interactionswith OFDI has been reviewed.

Viewing the OFDI images of the tissue during laser exposure provides anindication of the potential of this exemplary technique. With no laserexposure, the speckle pattern observed in OFDI remained constant overthe depth and transverse extent of the image. Under laser irradiation,the speckle pattern was observed to rapidly fluctuate in the localregion of the laser beam. In slow-motion viewing, we observed that thespeckle fluctuations began near the tissue surface and propagateddownward in time. To quantify these observations, the rate of speckledecorrelation for each depth point of the image 2410 shown in FIG. 6Bhas been determined. In particular, the depth-dependent width of thetemporal autocorrelation function of the OFDI intensity signal has beendetermined. Speckle decorrelation images were then generated bydisplaying the autocorrelation width using a grayscale lookup table. Theimage 2430 of FIG. 6D is the speckle decorrelation image correspondingto the images 2410 and 2420 of FIGS. 6B and 6C, respectively. The depthof the peak decorrelation 2431 rate (black band, denoted by arrows inFIG. 6D) can be observed to vary in correspondence with thetranslational rate of the sample and the depth of laser damage indicatedin histology. The consistency of this finding across samples ofesophagus and duodenum confirm that the depth of peak decorrelation rateis a quantifiable metric for determining the depth of laser injury.

Birefringence

As light propagates within materials, its polarization state can becomealtered if the index of refraction is non-isotropic. This effect isknown as birefringence. Many tissues, especially muscle and collagen,exhibit strong birefringence which is lost upon thermal heating anddenaturation (as described in publication 46). Polarization-sensitiveOCT (PS-OCT) techniques, methods and systems have been described forquantifying burn depth through measurements of birefringence loss. (Seepublications 52 and 53 identified below). In PS-OCT, two detectorchannels can be configured to receive orthogonal polarization states ofthe light returning from the sample. Birefringent samples induce adepth-dependent rotation of the polarization state, resulting in avariation in the percentage of the sample light detected in eachchannel. If the ratio of the two channels is displayed as a grayscale ina cross-sectional image, birefringence is observed as a characteristicbanding pattern.

For example, the apparatus of FIG. 4 can be modified to include agalvanometric scanner so that the OFDI beam may be repetitively scannedacross the surface of the tissue while the sample was held stationaryand the 1450 nm laser spot remained fixed on center, as shown in FIG.27. As shown in FIG. 27, the treatment light can be delivered through afirst collimator 2500 providing a treatment beam 2510 incident on thetissue 2550 that is covered by a cover slip 2540 and against a backing2560. The imaging light may be provided by a second collimator 2570producing an imaging beam 2580 that is directed by a galvo-mirror 2520through a lens 2530. This arrangement/system can be an exemplaryembodiment of a therapeutic monitoring system applicable to applicationsin dermatology. OFDI images or video of esophageal and duodenal tissueswere acquired during laser irradiation.

FIGS. 7A-7D show images of the representative data. In frames acquiredprior to laser irradiation, the layered esophageal structure can beobserved in the intensity image 2450 (see FIG. 7A) and characteristicbirefringence banding can be observed in the corresponding polarizationimage 2460 (see FIG. 7B). In frames acquired during laser exposure, theepithelial scattering intensity may be increased dramatically within the1.1 mm laser spot 2470 (see FIG. 7C), and the birefringence banding inthe corresponding polarization image 2480 (see FIG. 7D) can be lost.Reviewing the polarization moving images in slow-motion, a zone ofdecreased birefringence can be observed that may begin near the surfaceand propagated downward. These observations are generally consistentwith a downward propagating zone of denatured tissue. Measurements ofthe percent-loss of birefringence is a quantitative metric formonitoring laser thermal damage.

Scattering

Thermally induced changes to the microscopic structure of tissue canalter optical scattering. Since the signal in OFDI arises fromscattering and small changes can be detected over a large dynamic range,we investigated the use of scattering measurements for monitoringthermally induced changes in tissue. Scattering changes observed inimage 2460 of FIG. 7B may be representative of the preliminaryobservations in both duodenum and esophagus samples. In certain cases,it was determined that the significant scattering changes within theepithelium and relatively smaller changes in the underlying tissues ofthe muscularis mucosa and muscularis propria. For example, two potentialquantitative metrics for laser damage that could be obtained fromscattering measurements: changes in the depth-resolved scatteringintensity and changes in the depth-integrated scatting intensity.

Blood Flow

Laser therapy can to alter vessels and capillaries resulting indecreased blood flow (as described in publication 54 identified below).Since the esophageal mucosa is highly vascularized, monitoring changesin blood flow may provide an additional method for monitoring lasertherapy. An image 2490 of FIG. 8, acquired during our recent swinestudies, graphically illustrates the porcine esophageal vascularity.This exemplary image 2490 was generated by unwrapping the tubular imagedata to display the epithelial surface as if the esophagus waslongitudinally opened and pinned flat. The intensity data has beenintegrated over depth into the tissue. Although this type of large scalevisualization is a convenient way to map the vessels, it is possible touse a more sensitive and quantitative method/technique/system formeasuring blood flow. Doppler OCT (as described in publications 55 and56 identified below) has been demonstrated for visualizing andquantifying blood flow in tissue and has been investigated as anarrangement for assessing flow following laser therapy (as described inpublication 57 identified below). The Doppler measurements with OFDI (asdescribed in publication 24 identified below) have been described, andthe possibility of simultaneously measuring structure and flow in vivohas been reviewed.

A cross-sectional view of an exemplary image 2590 of FIG. 9 has beenacquired in the esophagus of a living swine and displays intensity as agrayscale and Doppler as a superimposed color. The coordinates (r,θ) ofthis data have been mapped to Cartesian coordinates (vertical,horizontal) for simplicity of display. This result was representative ofour observations at multiple locations in two swine. Additionally, intime-sequences of Doppler images, we clearly observed pulsatile flow.Summary of Monitoring Cause Effect Measurement Thermal denaturing ofFocal deformation Phase & Speckle cellular proteins and collagen Loss ofbirefringence Polarization ΔScattering Intensity Thermal coagulation ofLoss of blood flow Doppler flow & vessels Vascular Map

Based on the preliminary investigation, the proposed measurements wouldlikely be complementary: and the phase-shift and speckle decorrelation,which are only applicable during laser irradiation, may be moresensitive and provide greater spatial resolution. The changes inbirefringence, scattering and flow are persistent and could be appliedfor follow-up imaging after laser treatment.

Exemplary Control

In addition to monitoring for laser thermal injury, effective conformallaser therapy may use precise control over the volume of treated tissue.One exemplary approach to controlling treatment depth is to operatewithin the conditions for thermal confinement in order to minimizecollateral damage and to manipulate laser wavelength, power, andexposure time to control the depth of thermal injury. In the transversedimension (along the epithelial surface), thermal injury can becontrolled through the use of a raster-scanned, spatially-collimatedbeam. A flat-top beam with a diameter of 1-3 mm with well-defined edgesmay allow spatial control while also permitting therapy of largeepithelial areas through raster scanning. Exemplary laser controlparameters are described herein below in the context of Eq. 1. Thetemperature distribution of Eq. 1 generally applies only in the limit ofweak scattering.

Wavelength

From the temperature distribution of Eq. 1, it is evident that μ_(a)would likely be an optimal parameter for control over depth of laserinjury. Although μ_(a) is characteristic of the sample rather than anexternally controllable parameter, in this invention we exploit thewavelength dependence of μa to achieve depth control. In this invention,we target the absorption coefficient at longer wavelengths where waterabsorption dominates. Since the water content is approximately constantin epithelial tissues, thermal injury depth can be closely regulated bychanging the laser wavelength by small amounts. In the vicinity of thewater absorption band near 1.45 μm, absorption lengths (see graph 2595of FIG. 10) range from 0.3 mm to over 2 mm within a narrow spectralrange (1375 nm to 1430 nm). These lengths correspond well to thecharacteristic length scales appropriate for the treatment of epithelialdisease. A tunable laser, operable in the vicinity of the 1450 nm waterabsorption band can be used to control therapy through wavelengthtuning.

Power and Exposure Duration

Upon the review of Eq. 1, the absorption coefficient does more thancontrol the exponential depth decay of the temperature distribution;e.g., it also can control the amplitude. Since the amplitude term isalso dependent upon power density and exposure duration, these variablescan be used to normalize the amplitude while allowing the absorptioncoefficient to change.

Procedure Duration

In the evaluation of a proposed new therapy, it may be important toestimate the preferable procedure time and evaluate this estimate in thecontext of competing approaches and constraints specific to the clinicalsetting and patient acceptance. PDT is currently applied for thetreatment of BE in the endoscopy setting and requires procedure times onthe order of 20 minutes. For the exemplary conformal laser therapytechnique, the procedure performance time may be estimated by 2At/(πrv),where At is the treatment area, r is the laser spot radius, and v is thelaser spot scan velocity. For an esophageal treatment length of 60 mmand an esophageal diameter of 20 mm.

According to the exemplary embodiment of the present invention, acombined system can be provided which may allow for a controlled laserexcitation. In one exemplary embodiment, the exemplary system can beused endoscopically for conformal laser therapy capable ofcomprehensively treating epithelial lesions while minimizing collateraldamage to adjacent tissues.

Exemplary System Design

According to the exemplary embodiment of the present invention, a systemcan be provided for performing conformal laser therapy of epithelialdisease through a combination of monitoring and control. Since laserbeams can easily be shaped and spatially scanned and since margins inthe transverse plane (along the surface of the esophagus) are lesscritical, the primary challenge for achieving accurate control of lasertherapy is in limiting and adjusting the depth of laser damage. Based onthe modeling and analysis described above, it is possible to utilizelaser wavelength and power and scanning speed to vary the depth of laserdamage over a clinically significant range while not significantlyaltering the transverse extent of injury.

Exemplary Therapy Laser Arrangement

The laser wavelengths between approximately 1375 nm and 1430 nm canprovide absorption lengths ranging from over 2 mm to less than 0.3 mm.Semiconductor lasers can operate in this spectral range. Since suchlasers can be compact and environmentally stable, these laser can beeffectively used in clinical applications. Materials suitable for thisspecific wavelength range, however, may not be standard. A lessexpensive alternative for the early testing phase of exemplaryembodiments of the methods according to the present can be provided by asolid-state laser material, tetravalent chromium-doped YAG (Cr4+:YAG).For example, a tunability with this material over the spectral range of1340 nm-1570 nm can be implemented (as described in publications 58 and59 identified below). The exemplary design and construction of tunablesolid-state lasers that operate in the near infrared spectral range aredescribed in publications 60-65 identified below. An electromechanicalshutter, external to the laser resonator, can be used to turn on/off theexemplary laser.

Exemplary Benchtop System

An exemplary embodiment of a benchtop optical system according to thepresent invention may be provided that can be similar to the systemsshown in FIGS. 4 and 27 and described herein. For example, the OFDIsampling beam may be focused at the sample to a diameter of ˜25 μm. Theaxial location of the focus can be determined using a standard z-scantechnique, and may be registered within the OFDI cross-sectional image.The subsequent axial positioning of the samples within the OFDI imagewindow may ensure a constant focus location for all samples. Data may becollected with the two beams fixed with respect to each other and whilethe sample is translated perpendicular to the laser beam axis.

Exemplary Positioning and Registration of Laser and OFDI Beams

According to the exemplary embodiment of the present invention, theoffset between the OFDI beam and the center of the laser spot is notcritical for monitoring. OFDI data may be collected for various offsets(as depicted in FIG. 4) to determine the offset that yields the greatestindicated depth of thermal injury. This offset can then be used in allsubsequent studies and may be registered as follows. A small, low-power,short-duration epithelial burn may be induced on the surface of thesample while the sample is held fixed (non-translating). As shown inFIG. 7, the increase in epithelial scattering can be readily observed inOFDI and is spatially localized as defined by the laser beam profile.Although not illustrated in FIG. 4, the OFDI beam can be relayed to thefocusing lens by a pair of galvanometers that provide two-dimensionalscanning. The galvanometers may be used to generate an en face OFDIimage of the sample and the epithelial burn may appear as a circle ofincreased scattering. The galvanometers can then be positioned and fixedso that the OFDI beam is positioned with the desired offset (asschematically shown in FIG. 4).

Exemplary Wavelength Scaling

One of the purposes of this experiment is to test the exemplarytechnique and method of wavelength variation and power normalizationaccording to the present invention for achieving clinically relevantvariation in the depth of laser damage. Laser wavelength may be variedfrom about 1375 nm to 1405 nm in 2 nm steps with laser spot size andscanning speed held constant. For each wavelength, the laser power maybe adjusted so that the product P_(d)⊕μ_(a) in Eq. 1 can be maintainedas constant. This should yield lines of constant width and with damagedepth ranging from approximately 0.25 to 1.5 mm.

Exemplary Scanning Velocity Scaling

One exemplary embodiment according to the present invention foraffecting therapeutic depth may include scaling the scan velocity. Forexample, the therapy beam scan speed can be varied from 1 mm/s to 5mm/s. Slower scan speeds allow time for heat to conduct to deeper areasof the tissue, producing deeper therapy.

Exemplary Positioning and Registration of Laser and OFDI Beams

To ensure accurate therapeutic monitoring, the spatial relationshipbetween the OFDI sampling beam and the laser spot can be controlled.

Exemplary Endoscopic Probe Designs

One exemplary embodiment of the present invention can include anendoscopic probe for comprehensive, volumetric imaging and simultaneouslaser therapy, as shown in FIG. 11. For example, two beam relay optics2640 a and 2640 b may be used, one of which conveys imaging light 2640 band the other therapy light 2640 a. These relay optics are placed withina housing 2630 that is enclosed within a first transparent sheath 2600.A balloon centration mechanism (as described above) 2620 may be used tomaintain a constant distance between the optical probe 2630 and thetissue surface 2610. Laser light and the OFDI beam may be deliveredthrough separate optical fibers 2641 a and 2641 b. Each fiber may haveits own relay optics to produce independently controllable spot sizes. Afurther exemplary embodiment of the present invention can include theserelay optics designed to produce overlapping spots. The optical fibersand distal optics may be housed in a wound-wire drive shaft and placedinside a balloon-centering probe identical to the balloon sheaths.

Longitudinal scans can be activated using a computer controlledtranslation stage attached to the proximal end of the drive shaft. Thisexemplary arrangement may be the same as the arrangement which can beused for the pull-back esophageal imaging of our preliminary studies. Amanual rotation of the drive shaft may be possible, as is automatedrotation using an exemplary rotary coupler 2900 shown in FIG. 13. In oneexemplary embodiment of the present invention, an endoscopic system mayscreen for disease over large fields-of-view, accurate monitoring oflaser-tissue interaction, and precisely control laser therapy. One ofthe applications of such exemplary embodiment may be the identificationand treatment of epithelial cancers and their precursors. In a furtherexemplary embodiment, the system can incorporate procedures and softwaremodules than can directly link screening, monitoring, and control.

In yet another exemplary embodiment, the system may be used to generatea high-resolution, 3-dimensional map of the entire distal esophagus tofacilitate therapeutic planning. Thereafter, the use may be presentedwith a ‘live’ cross-sectional image comprising three sections, asillustrated in FIG. 14. A right section 2700 of the image may be thetissue immediately ahead of the therapeutic laser, the center 2730 ofthe image may be the location of the laser with a marker 2740designating the zone of therapy, and the left section 2710 of the imagemay be the tissue that has already been treated. Since the three beamsmay be continuously scanning, the tissue may appear to move from rightto left as the image updates. The user (e.g., an endoscopist) mayoperate a control servo to start/stop the treatment and increase ordecrease the depth of therapy. By viewing the zone of treatment 2710 andlooking ahead to the untreated tissue 2700, the user may be able tosteer and conform the region of laser therapy to the desired target.

An exemplary embodiment of the endoscopic probe for imaging, monitoringand laser therapy through a centering balloon according to the presentinvention is shown in FIG. 12. This exemplary probe can rotate to scanthe esophagus circumferentially and may be longitudinally translated ata slower rate to define segments for therapy. This probe may include,e.g., three or more optical channels: a first channel 2800 c for imagingthe tissue prior to laser irradiation, a second channel 2800 b fortreatment, and a third channel 2800 a for monitoring. Each optical fibermay be separately imaged transversely onto the esophageal wall throughthe balloon. The alignment of the resulting output beams may be suchthat, upon rotation in the clockwise direction, the imaging beamprecedes the treatment beam sufficiently so that non-treated tissue maybe sampled. The monitoring beam may be aligned to fall within the laserspot. Following initial alignment of the three beams, the optics may bebonded together with epoxy, and the alignment may be fixed.

Exemplary Rotary Junction

An exemplary rotational coupler according to the present invention whichcan connect the three-channel catheter to the OFDI system is shown inFIG. 13, and can be referred to “watch-spring” rotary junction (since itcan rely on two concentric spools). For example, as the inner spool 2900rotates in one direction, optical fiber is wound from the outer spool2910 onto the inner spool 2900. On reversing the direction, the fibercan unwind from the inner spool. Ribbon optical fiber may be used andtwo parallel plates 2920 with a gap matched to the ribbon width canensure that the windings remain flat and do not bind. The plates may besufficiently large so that up to, e.g., 100 rotations may be possibleprior to requiring counter rotation. With a 1 mm laser spot, fulltreatment of 6 cm long esophageal segments may be 60 revolutions. Aplate diameter of less than 10 cm can be used. In addition toaccommodating three optical channels, this exemplary embodiment of thearrangement and system according to the present invention can avoid theloss and back-reflections that arise from air-gap couplers.

Exemplary High-Speed Acquisition and Processing

A further exemplary embodiment of the system and arrangement accordingto the present invention can utilize, e.g., a high-speed imaging system.The exemplary embodiment of the digital acquisition and processingsystem can be based on VME-bus hardware for acquiring, processing andstoring the OFDI signals in real-time. The exemplary components of suchexemplary system and arrangement may comprise a VME chassis containinghigh-speed digitizers residing on a single-board computer andfiber-optic links to a RAID storage array. This exemplary system andarrangement can be controlled via a host processor (e.g., a personalcomputer). The analog OFDI signals may be digitized using widebandreceivers (e.g., 12 bit, 210 MS/s) with integratedfield-programmable-gate-array (FPGA) processors. Processing power,resident on the acquisition board, may be importance since the raw datarate may be 800 MB/s for the two polarization channels of the OFDIsystem. The FPGA processor can be configured or programmed to transformeach polarization channel from the frequency-domain to a 1024-elementarray representing reflectivity versus depth (one A-line). This data canbe passed to the single-board computer for subsequent processing and forcombining the two channels prior to transferring the final data to aRAID array of hard drives. The final data storage rate may be, e.g., 400MB/s. By striping the data across multiple hard drives, this data ratecan be continuously sustained.

Software on a processing arrangement in accordance with an exemplaryembodiment of the present invention can permit a user control over theexemplary system, and may enable a display of the images at adown-sampled rate in real-time. For example, the exemplary system can beused in two exemplary modes: a burst mode at full data rate, andcontinuous mode at half data rate. The exemplary endoscopic system andarrangement can include the components and software described above, andadditional procedures (e.g., software) can be provided to program boththe FPGA processor and single-board computer to facilitate thecomputations of phase-shift, birefringence, speckle, and Doppler signalsin real-time. The combined computational capacity of the Vertex 4 ProFPGA and quad G4 single-board computers may be ample for displaying themonitoring signal in real-time.

Exemplary Laser

Using Eq. 1, the spot size while maintaining a constant scan velocitycan be doubled by using a 4-fold increase in the laser power in order tomaintain a constant temperature distribution in the tissue. Doubling thescan velocity at a constant spot size should use a doubled laser power.One exemplary embodiment of a laser arrangement in accordance with thepresent invention can utilize a single-emitter semiconductor laserdiode. Previous devices have provided more than 3 W of laser power overthis spectral range using a simple external cavity design including adiffraction grating for wavelength control. The laser power andwavelength may be controlled via the host processing arrangement of theOFDI system based on an analog signal from a potentiometer. Thepotentiometer may be a hand-held dial that the user (e.g., anendoscopist) may use to increase or decrease the depth of laser damage.

Exemplary User Interface

The exemplary embodiment of the system and method according to thepresent invention can provide a user interface to the operator thatincludes a cross-sectional image of the tissue. The image may becontinuously updated and may include views of treated and upcoming,untreated tissue as well as a designation for the zone of lasertreatment as determined by the monitoring procedures. The user interfacemay be programmed on the host processing arrangement, and can usecomputational results from the FPGA processor and single-board computer.Images and laser parameters may be archived to the RAID array.

In one further exemplary embodiment of the present invention, theimaging system/arrangement 100 can be connected to a three-fiber probeusing an optical switch 115 as shown in a block diagram of FIG. 15. Theexemplary probe, such as that described above with reference to FIG. 12,can include two imaging fibers and one therapy fiber. The switch 115 canalternately couple imaging light to one of the two imaging fibers 120 a,120 b which can be used to acquire re-therapy images and, e.g.,during-therapy imaging. A therapeutic light source 105 may connectdirectly to the therapy fiber 125 c. The fibers can be connected to thecatheter 130, which can be, e.g., the exemplary catheter shown FIG. 12.A signal from the imaging system 100 can control the state of theoptical switch 115.

In yet another exemplary embodiment according to the present inventionshown in FIG. 16, the exemplary imaging system/arrangement 200 can becoupled to an exemplary three-port catheter such as one shown in FIG. 12via an optical splitter 215 that can couple light to both of two imagingfibers 220 a, 220 b. This exemplary imaging system can separate theimage signal from each using path-length encoding techniques. Togenerate the differential path length, an optical delay 235 may beplaced in one fiber 220 b or multiple fibers. The therapeutic lightsource 205 can be coupled directly or indirectly to the therapy fier 225c of the catheter.

In still another exemplary embodiment of the exemplary imagingsystem/arrangement 800 according to the present invention shown in FIG.17, light may be combined with the therapy source 805 using a singlewavelength-division multiplexer 810. The combined light may be coupledto a single fiber rotary coupler, and then to an exemplary single fibercatheter such as the catheter shown in FIG. 21.

In a further exemplary embodiment of the imaging system/arrangement 900according to the present invention shown in FIG. 18, light may becombined with the therapy light 905 using a cladding mode coupler thatcouples the imaging system 900 light from the single mode fiber 901 tothe single mode core of a dual-clad fiber 911 and the therapy light froma multimode fiber 906 to the cladding mode of a dual-clad fiber 911.

FIG. 19 shows exemplary connections between a system 400 with threeoutput fibers 405 a, 405 b, 405 c, such as one shown schematically in,e.g., FIGS. 15 and 16, and a three-port catheter 415, such as one shownin FIG. 12 via a multi-channel rotary coupler 410, such as one shown inFIG. 13.

FIG. 20 shows a schematic diagram of an exemplary system 300 accordingto the present invention in which a single fiber 305 containing both theimaging light and therapy light may be coupled to a single-channelrotary coupler 310. For example, after the rotary coupler 310, the lightcan be divided by a wavelength-division multiplexer (WDM) 330 thatseparates the imaging light onto a first fiber 332 and the therapy lightonto a second fiber 331. The imaging light may further be separatedusing an optical splitter 335 that greats two imaging ports 336 a and336 b. The fibers 31, 336 a, 336 b can be connected to a three-portcatheter 325 design such as that shown in FIG. 12. The catheter section320 may be flexible allowing endoscopic insertion and the sectioncontaining a WDM 330 and a splitter 335 can be enclosed within a rigidtube 315 to protect these components.

FIG. 21 shows a side view of an exemplary embodiment of a distal opticsarrangement according to the present invention that may create a singleimaging beam 1125 and a separate therapy beam 1120 from a single-modefiber 1101. For example, the light from the fiber containing bothimaging and therapy light can first be focused by a first GRIN lens1100. The light is then passed into a wavelength-division multiplexingprism 1105 that can direct the therapy light wavelengths upward tocreate the therapy beam 1120, and transmits the imaging lightwavelengths to a second GRIN lens 1110, which can alternately focus theimaging light and directs it to a final prism 1115 that directs theimaging beam 1125 upward. The angle of the prisms 1105 and 1115 may besuch that the beams are made to overlap at the appropriate distance fromthe device.

FIG. 22 shows side and front views of an exemplary embodiment of athree-port catheter in accordance with the present invention. Theexemplary catheter can include three fibers 1005 that connect to threesets of focusing optics 1035 contained in a V-groove 1020 inside ahousing 1040. The focusing optics can provide beam focusing.Micro-prisms 1025 can redirect the optical beam upward through acylindrical lens 1030 that corrects for astigmatism induced by thetransparent sheath 1000. A balloon 1010 centration mechanism may be usedto maintain centering of the optics 1035 within the luminal tissue 1015.In the end-view, the monitoring beam 1050 c, therapy beam 1050 b, andpre-imaging beam 1050 a can be seen. The housing 1040 can be adapted torotate by a multichannel rotary coupler such as one shown in FIG. 13.

FIG. 23 shows a side view of an exemplary embodiment of a catheter inaccordance with the present invention which can utilize a miniaturemotor 1260 to achieve rotation of the imaging beam. For example, themotor 1260 can be enclosed within a transparent sheath 1235. Therotation of the motor shaft can rotate a prism 1220. The imaging lightcan be coupled to the distal optics via a fiber 1210, where the lightcan be focused by focusing optics 1215, and reflected onto the prism1220 by a reflector 1225. The rotation of the prism 1220 sweeps theimaging beam circumferentially. The motor electrical connections 1205can be achieved through the same lumen as the fiber 1210. The therapylight is coupled to the distal optics on fiber 1200. This therapy lightmay be focused using focusing optics 1250, and directed sideways byprism 1245 at a fixed rotational angle relative to the inner sheath1235. The imaging beam thus sweeps through the fixed therapy spot. Thetranslation of the therapy spot is achieved by rotation of the entireinner sheath 1235 within the outer sheath 1240. This exemplary rotationcan be achieved through the use of a multi-channel rotary coupler suchas a coupler shown in FIG. 13. The catheter can use a balloon 1255 forcentration of an optical core 1230.

FIG. 24 shows a block diagram of an exemplary embodiment of a lasertherapy source according to the present invention with wavelengthtunability utilizing a low power wavelength tunable source 600, followedby a broadband booster amplifier 605 to increase the optical power.

FIG. 25 shows a block and functional diagram of an exemplary embodimentof a laser therapy source incorporating multiple laser diodes 500 a, 500b, 500 c, 500 d at difference wavelengths and polarizations, and theexemplary procedure to implement such arrangement. For example, thelight can be combined by the polarization multiplexers 505 a, 505 b andwavelength division multiplexers 510 to a single mode fiber 515.Optionally, the light can be coupled to a multimode fiber 520. A fastmode scrambler 525 can be used to scramble the transverse mode patternoutput from the multi-mode fiber at a fast rate. Other sourcearrangements which can output light on a single mode fiber can use asimilar design to couple light to a multimode fiber.

FIG. 26 shows an exemplary embodiment of a therapy light source and usethereof according to the present invention. For example, a laser diodebar 700 can be used with multiple wavelengths 701 a-g. Each waveguidecan be coupled to a free-space laser cavity through a lens apparatus 705and a grating 710 and a partially reflecting end mirror 715. Because ofthe wavelength dispersion of the grating, the laser formed by eachwaveguide lases at a different wavelength. Thus, by adjusting the drivecurrent to each of the waveguides 701 a-g, the laser output 720 powerand spectral shape can be adjusted.

In a further exemplary embodiment according to the present invention, asingle OFDI system can be modified to facilitate a detection of both theimaging and monitoring signals through the use of acousto-opticfrequency shifters as shown in FIG. 28. For example, a wavelength sweptlaser source 3000 can be separated by a first splitter 3020 to produce asample arm path and reference arm path. The sample arm path is furtherseparated by a second splitter 3030, with a first output of thissplitter being directed to a first frequency shifter 3061 and a secondoutput being directed to a second frequency shifter 3060. Each of thefrequency shifters can be driven with a separate frequency. The lightfrom the first frequency shifter 3061 can be coupled through an opticalcirculator 3071 to the imaging fiber 3072 of a three-fiber rotarycoupler 3110 like that shown in FIG. 13. The light from the secondfrequency shifter 3060 may be coupled through a circulator 3070 to amonitoring fiber 3073 of the same rotary coupler.

A separate therapy laser 3010 can be coupled to the third therapy fiber.The returned light on the imaging fiber 3072 and monitoring fiber 3073may be recombined at an optical combiner 2080, and mixed with thereference arm light at a second combiner 3090 with the output directedto a set of detectors 3100. Due to the frequency shifters, theinterference signal due to the imaging light and the interference signaldue to the monitoring light are encoded at separate carrier frequenciesand can be separated through conventional frequency domain techniques.

FIG. 29A shows a flow diagram of an exemplary embodiment of a method forobtaining information associated with at least one portion of a sampleaccording to the present invention. For example, a temperature changecan be caused in the portion of the sample in step 3100. At least onefirst electro-magnetic radiation can be forwarded to a section near orin the portion of the sample in step 3110. A deformation of the sectioncan be identified at a plurality of depths as a function of (i) a phaseof at least one second electro-magnetic radiation provided from thesection, and/or (ii) a rate of change of the phase and/or an amplitudeof the second electro-magnetic radiation in step 3120.

FIG. 29B shows a flow diagram of another exemplary embodiment of themethod for controlling a temperature distribution in the sampleaccording to the present invention. For example, an electro-magneticradiation can be provided to the section in the sample at a particularwavelength in step 3130. The temperature distribution can be controlledby modifying the particular wavelength of the electro-magnetic radiationwhen the electro-magnetic radiation can be provided to the section instep 3140.

FIG. 29C illustrates a flow diagram of yet another exemplary embodimentof the method for applying a laser radiation to at least one portion ofa biological structure according to the present invention. For example,a beam of the laser radiation can be provided to the portion in step3150, whereas a cross-sectional area of the beam is at most about1/10^(th) of an entire area of the at least one portion. In step 3160,the beam can be applied to the portion (I) based on a predeterminedpattern, (II) while modulating a wavelength of the laser radiation,and/or (III) while monitoring a depth of the application of the laserradiation.

EXEMPLARY REFERENCES

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The foregoing merely illustrates the principles of the invention.Various modifications and alterations to the described embodiments willbe apparent to those skilled in the art in view of the teachings herein.Indeed, the arrangements, systems and methods according to the exemplaryembodiments of the present invention can be used with and/or implementany OCT system, OFDI system, SD-OCT system or other imaging systems, andfor example with those described in International Patent ApplicationPCT/US2004/029148, filed Sep. 8, 2004, U.S. patent application Ser. No.11/266,779, filed Nov. 2, 2005, and U.S. patent application Ser. No.10/501,276, filed Jul. 9, 2004, the disclosures of which areincorporated by reference herein in their entireties. It will thus beappreciated that those skilled in the art will be able to devisenumerous systems, arrangements and methods which, although notexplicitly shown or described herein, embody the principles of theinvention and are thus within the spirit and scope of the presentinvention. In addition, to the extent that the prior art knowledge hasnot been explicitly incorporated by reference herein above, it isexplicitly being incorporated herein in its entirety. All publicationsreferenced herein above are incorporated herein by reference in theirentireties.

1. A process for obtaining information associated with at least oneportion of a sample, comprising: causing a temperature change in the atleast one portion of the sample; forwarding at least one firstelectro-magnetic radiation to a section near or in the at least oneportion of the sample; and identifying a deformation of the section at aplurality of depths as a function of at least one of (i) a phase of atleast one second electro-magnetic radiation provided from the section,or (ii) a rate of change of at least one of the phase or an amplitude ofthe at least one second electro-magnetic radiation.
 2. The processaccording to claim 1, further comprising: generating an interferometricsignal associated with the at least one second electro-magneticradiation; and determining the phase of the at least one secondelectro-magnetic radiation using the interferometric signal.
 3. Theprocess according to claim 2, further comprising measuring theinterferometric signal as a function of a wavelength of the at least onesecond electro-magnetic radiation.
 4. The process according to claim 1,wherein the at least one first electro-magnetic radiation has awavelength that varies over time.
 5. The process according to claim 1,wherein the temperature change is caused using a laser arrangement. 6.The process according to claim 1, further comprising defining a borderbetween the at least one changed portion and an unchanged portion of thesample as a function of the information associated with the deformation.7. The process according to claim 6, wherein the sample is a biologicalstructure, and wherein the at least one changed portion is at least oneof denatured, damaged or destroyed.
 8. The process according to claim 1,further comprising: generating an interferometric signal associated withthe at least one second electro-magnetic radiation; and determining theamplitude of the at least one second electro-magnetic radiation usingthe interferometric signal.
 9. The process according to claim 8, furthercomprising measuring the interferometric signal as a function of awavelength of the at least one second electro-magnetic radiation. 10.The process according to claim 1, wherein the electro-magnetic radiationis forwarded to the section in the sample at a particular wavelength;and further comprising: during the forwarding of the at least one firstelectro-magnetic radiation, controlling a temperature distribution inthe sample by modifying the particular wavelength of theelectro-magnetic radiation.
 11. The process according to claim 1,wherein step (b) comprises applying a beam of the laser radiation of theelectro-magnetic radiation to the section, wherein a cross-sectionalarea of the beam is at most about 1/10^(th) of an entire area of thesection, and further comprising: applying the beam to the at least oneportion at least one of (i) based on a predetermined pattern, (ii) whilemodulating a wavelength of the laser radiation, or (iii) whilemonitoring a depth of the application of the laser radiation
 12. Aprocess for controlling a temperature distribution in a sample,comprising: a) providing an electro-magnetic radiation to a section inthe sample at a particular wavelength; and b) during step (a),controlling the temperature distribution by modifying the particularwavelength of the electro-magnetic radiation.
 13. The process accordingto claim 12, further comprising: c) prior to step (a), causing atemperature change in at least one portion of the sample which is nearor in the section of the sample; and d) identifying a deformation of theat least one portion at a plurality of depths as a function of at leastone of (i) a phase of at least one further electro-magnetic radiationprovided from the at least one portion, or (ii) a rate of change of atleast one of the phase or an amplitude of the at least one furtherelectro-magnetic radiation.
 14. The process according to claim 12,wherein step (b) comprises applying a beam of the laser radiation of theelectro-magnetic radiation to the section, wherein a cross-sectionalarea of the beam is at most about 1/10^(th) of an entire area of thesection, and further comprising: e) applying the beam to the at leastone portion at least one of (i) based on a predetermined pattern, (ii)while modulating a wavelength of the laser radiation, or (iii) whilemonitoring a depth of the application of the laser radiation
 15. Theprocess according to claim 12, wherein the modification to theparticular wavelength changes a distribution of damage in at least oneportion of the sample.
 16. The process according to claim 12, whereinthe temperature distribution is further controlled by modifying a powerof the electro-magnetic radiation.
 17. The process according to claim12, wherein the particular wavelength is modified to be in a range ofapproximately at least one of (i) about 1.35 μm to 1.5 μm or (ii) about1.7 μm to 2.2 μm.
 18. The process according to claim 12, wherein thetemperature distribution is substantially due to an absorption of theelectro-magnetic radiation by water.
 19. The process according to claim12, wherein the electro-magnetic radiation is provided by at least oneof a thulium laser amplifier arrangement or an erbium laser amplifierarrangement.
 20. The process according to claim 12, wherein a rate atwhich the particular wavelength is modified is greater that about 10 nmper second.
 21. The process according to claim 12, wherein theparticular wavelength is modified in a non-random manner.
 22. A systemfor obtaining information associated with at least one portion of asample, comprising: a first arrangement configured to cause atemperature change in the at least one portion of the sample; a secondarrangement configured to forward at least one first electro-magneticradiation to a section near or in the at least one portion of thesample; and a third arrangement configured to identify a deformation ofthe section at a plurality of depths as a function of at least one of(i) a phase of at least one second electro-magnetic radiation providedfrom the section, or (ii) a rate of change of at least one of the phaseor an amplitude of the at least one second electro-magnetic radiation.